The present invention is directed to compounds useful as delta-opioid and mu-opioid receptor modulators. More particularly, the present invention is directed to 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives useful as delta-opioid or mu-opioid receptor modulators.
WO 97/23466 describes compounds as having an analgesic effect of a general and one preferred formula: 
WO 98/28270 describes compounds as having an analgesic effect of a general and one preferred formula: 
WO 98/28275 describes compounds as having an analgesic effect of a general and one preferred formula: 
Amide derivatives of 3-aminotropane have been prepared and described as having potential pharmacological activity (Gutkowska, B., et al., Acta Pol. Pharm., 1984, 41(6), 613-617), of the formula: 
WO 93/15062 describes compounds as delta-opioid (xcex4-opioid) and mu-opioid (xcexc-opioid) receptor agonists of (approximately) the general formula: 
The synthesis and binding affinities for 4-Diarylaminotropane compounds as xcex4-opioid agonists have been described (Boyd, R. E., Carson, J. R., Codd, E. E., Gauthier, A. D., Neilson, L. A and Zhang, S-P., Biorg. Med. Chem. Lett., 2000, 10: 1109-1111) of the general formula: 
wherein R is hydrogen, methyl, propyl, hexyl, 2-ethylbutyl, allyl, 3,3-dimethallyl, cyclohexylmethyl, phenethyl, phenylpropyl, 2,2-diphenylethyl, 3,4-dimethoxyphenethyl, 4-fluorophenethyl, 2-furylmethyl, 3,4-methylenedioxybenzyl, cyano and X is N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-phenylamino, N-ethyl-N-(4-methyl)benzylamino, N-butyl-N-ethylamino, N-butyl-N-propylamino, [N-ethyl-N-(2-methyl)allyl]amino, hydroxy, O-t-butyl and 1-pyrrolidinyl; and, Y is hydrogen, methoxy and methylthio.
Other selective 4-[(8-alkyl-8-azabicyclo[3.2.1] octyl-3-yl)-3-arylanilino]-N,N-diethylbenzamide xcex4-opioid ligands have also been described (Thomas, J. B., Atkinson, R. N., Rothman, R. B., Burgess, J. P., Mascarella, S. W., Dersch, C. M., Xu, H. and Carroll, F. I., Biorg. Med. Chem. Lett., 2000, 10: 1281-1284).
The present invention is directed to compounds useful as delta-opioid and mu-opioid receptor modulators. More particularly, the present invention is directed to delta-opioid and mu-opioid receptor modulators.
It is an object of the present invention to provide 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives useful as xcex4-opioid or xcexc-opioid receptor modulators. It is also an object of the present invention to provide xcex4-opioid and xcexc-opioid receptor selective agonists as analgesics having reduced side-effects. It is another object of the present invention to provide xcex4-opioid and xcexc-opioid receptor selective antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, having reduced side-effects. It is also another object of the present invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as a xcex4-opioid or xcexc-opioid receptor modulator. It is a further object of the present invention to provide a useful pharmaceutical composition comprising a xcex4-opioid or xcexc-opioid receptor modulator compound of Formula (I) in combination with a xcexc-opioid receptor modulator or a xcex4-opioid or xcexc-opioid receptor modulator compound of Formula (I) wherein the combination has a synergistic therapeutic effect.
The present invention provides an opioid receptor modulator compound selected from the group consisting of a xcex4-opioid and a xcexc-opioid receptor modulator compound of Formula (I): 
wherein:
R1 is selected from the group consisting of hydrogen, C1-8alkyl, halo1-3(C1-8)alkyl, C2-8alkenyl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, C1-8alkoxy(C2-8)alkynyl, cycloalkyl, cycloalkyl(C1-8)alkyl, cycloalkylcarbonyl(C1-8)alkyl, cycloalkyl(C2-8)alkenyl, cycloalkyl(C2-8)alkynyl, heterocyclyl, heterocyclyl(C1-8)alkyl, heterocyclylcarbonyl (C1-8)alkyl, heterocyclyl(C2-8)alkenyl, heterocyclyl(C2-8)alkynyl, aryl, aryl(C1-8)alkyl, arylcarbonyl(C1-8)alkyl, aryl(C2-8)alkenyl, aryl(C2-8)alkynyl, arylaminocarbonyl(C1-8)alkyl, heteroaryl(C1-8)alkyl, heteroarylcarbonyl(C1-8)alkyl, heteroaryl(C2-8)alkenyl, heteroaryl(C2-8)alkynyl, heteroarylaminocarbonyl(C1-8)alkyl, (R1a)2xe2x80x94Nxe2x80x94(C1-8)alkyl, R1axe2x80x94Oxe2x80x94(C1-8)alkyl, R1axe2x80x94Sxe2x80x94(C1-8)alkyl, R1axe2x80x94SOxe2x80x94(C1-8)alkyl and R1axe2x80x94SO2xe2x80x94(C1-8)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
R1a is independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy(C1-8)alkyl, hydroxy(C1-8)alkyl, halo1-3(C1-8)alkyl, halo1-3(C1-8)alkoxy(C1-8)alkyl, C2-8alkenyl, C2-8alkynyl, cycloalkyl, cycloalkyl(C1-8)alkyl, heterocyclyl, heterocyclyl(C1-8)alkyl, heterocyclyl(C1-8)alkenyl, heterocyclyl(C1-8)alkynyl, aryl, aryl(C1-8)alkyl, aryl(C1-8)alkenyl, aryl(C1-8)alkynyl, arylcarbonyl(C1-8)alkyl, heteroaryl, heteroaryl(C1-8)alkyl, heteroaryl(C1-8)alkenyl, heteroaryl(C1-8)alkynyl and heteroarylcarbonyl(C1-8)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
R2 is selected from the group consisting of aryl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of xe2x80x94(CH2)3-5xe2x80x94 and xe2x80x94O(CH2)1-3Oxe2x80x94;
R3 is selected from the group consisting of aryl and heteroaryl optionally substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of xe2x80x94(CH2)3-5xe2x80x94 and xe2x80x94O(CH2)1-3Oxe2x80x94;
A is selected from the group consisting of xe2x80x94C(xe2x95x90X)xe2x80x94 and xe2x80x94SO2xe2x80x94;
X is selected from the group consisting of O and S;
Z is selected from the group consisting of xe2x80x94O(R4) and xe2x80x94N(R5)(R6);
R4 is selected from the group consisting of hydrogen, C1-8alkyl (optionally substituted with one to three halogen substituents), C1-8alkoxy(C1-8)alkyl, C2-8alkenyl, cycloalkyl, cycloalkyl(C1-8)alkyl, heterocyclyl, heterocyclyl(C1-8)alkyl, aryl, aryl(C1-8)alkyl, heteroaryl, heteroaryl(C1-8)alkyl, amino(C1-8)alkyl, C1-8alkylamino(C1-8)alkyl, di(C1-8)alkylamino(C1-8)alkyl and hydroxy(C1-8)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, xe2x80x94OCH2Oxe2x80x94, xe2x80x94O(CH2)2Oxe2x80x94, trifluoromethyl, halogen, hydroxy and cyano; and,
R5 and R6 are independently selected from the group consisting of hydrogen, C1-8alkyl (optionally substituted with one to three halogen substituents), C1-8alkoxy(C1-8)alkyl, C2-8alkenyl, cycloalkyl, cycloalkyl(C1-8)alkyl, heterocyclyl, heterocyclyl(C1-8)alkyl, aryl, aryl(C1-8)alkyl, heteroaryl, heteroaryl(C1-8)alkyl, amino(C1-8)alkyl, C1-8alkylamino(C1-8)alkyl, di(C1-8)alkylamino(C1-8)alkyl, aminoimino, aminocarbonyl, aminocarbonyl(C1-8)alkyl, aryloxycarbonylamino(C1-8)alkyl, heteroaryloxycarbonylamino(C1-8)alkyl, hydroxy(C1-8)alkyl and trifluoro(C1-4)alkoxy; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, xe2x80x94OCH2Oxe2x80x94, xe2x80x94O(CH2)2Oxe2x80x94, trifluoromethyl, halogen, hydroxy and cyano; alternatively, R5 and R6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety optionally substituted with one to four substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy and cyano;
and pharmaceutically acceptable enantiomers, diastereomers and salts thereof.
Embodiments of a compound of Formula (I) include those compounds wherein, preferably, R1 is selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, cycloalkyl, cycloalkyl(C1-8)alkyl, heterocyclyl, heterocyclyl(C1-8)alkyl, heterocyclylcarbonyl(C1-8)alkyl, aryl(C1-8)alkyl, arylcarbonyl(C1-8)alkyl, aryl(C2-8)alkynyl, arylaminocarbonyl(C1-8)alkyl, heteroaryl(C1-8)alkyl, (R1a)2xe2x80x94Nxe2x80x94(C1-8)alkyl and R1axe2x80x94Oxe2x80x94(C1-8)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, hydroxy and cyano.
More preferably, R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl, butenyl, allyl, 3,3-dimethallyl, cyclopropyl, cyclopropyl(C1-3)alkyl, cyclohexyl, cyclohexyl(C1-3)alkyl, pyrrolidinyl, pyrrolidinyl(C1-3)alkyl, 1,3-dioxolanyl(C1-3)alkyl, 2-imidazolinyl, 2-imidazolinyl(C1-3)alkyl, imidazolidinyl, imidazolidinyl(C1-3)alkyl, 2-pyrazolinyl, 2-pyrazolinyl(C1-3)alkyl, pyrazolidinyl, pyrazolidinyl(C1-3)alkyl, piperidinyl, piperidinyl(C1-3)alkyl, morpholinyl, morpholinyl(C1-3)alkyl, thiomorpholinyl, thiomorpholinyl(C1-3)alkyl, piperazinyl, piperazinyl(C1-3)alkyl, [4-(C1-3)alkyl-5-oxo-1,4-dihydrotetrazol-1-yl](C1-3)alkyl, piperonyl, (1,3-benzodioxol-5-yl)(C2-3)alkyl, (2,3-dihydro-1,4-benzodioxin-6-yl)carbonyl(C1-3)alkyl, (3,4-dihydro-2H-1,5-benzodioxepin-7-yl)carbonyl(C1-3)alkyl, benzyl, phenyl(C2-3)alkyl, phenyl(C2-3)alkynyl, diphenyl(C1-3)alkyl, phenylcarbonyl(C1-3)alkyl, phenylaminocarbonyl(C1-3)alkyl, furyl(C1-3)alkyl, thienyl(C1-3)alkyl, pyrrolyl(C1-3)alkyl, oxazolyl(C1-3)alkyl, thiazolyl(C1-3)alkyl, imidazolyl(C1-3)alkyl, pyrazolyl(C1-3)alkyl, isoxazolyl(C1-3)alkyl, isothiazolyl(C1-3)alkyl, 1,2,3-oxadiazolyl(C1-3)alkyl, 1,2,3-triazolyl(C1-3)alkyl, 1,3,4-thiadiazolyl(C1-3)alkyl, pyridinyl(C1-3)alkyl, pyridazinyl(C1-3)alkyl, pyrimidinyl(C1-3)alkyl, pyrazinyl(C1-3)alkyl, 1,3,5-triazinyl(C1-3)alkyl, indolyl(C1-3)alkyl, benzo[b]furyl(C1-3)alkyl, benzo[b]thienyl(C1-3)alkyl, (R1a)2xe2x80x94Nxe2x80x94(C1-3)alkyl and R1axe2x80x94Oxe2x80x94(C1-3)alkyl; wherein pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are optionally substituted with one to three substituents selected from oxo; and, wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, butoxy, chlorine, fluorine, hydroxy and cyano.
Most preferably, R1 is selected from the group consisting of hydrogen, methyl, n-propyl, n-butyl, allyl, 3,3-dimethallyl, cyclopropylmethyl, cyclohexylethyl, 2-(4-ethyl-5-oxo-1,4-dihydrotetrazol-1-yl)ethyl, piperonyl, 2-(1,3-benzodioxol-5-yl)ethyl, 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl, 2-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-2-oxoethyl, benzyl, phenethyl, phenylpropyl, phenoxyethyl, phenylcarbonylmethyl, phenylcarbonylethyl, phenylaminocarbonylmethyl, thienylmethyl, thienylethyl, imidazolylmethyl, pyridinylmethyl and indolylethyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of methoxy, fluorine, hydroxy and cyano.
Embodiments of a compound of Formula (I) include those compounds wherein, preferably, R1a is independently selected from the group consisting of hydrogen, C1-8alkyl and aryl; wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylcarbonylamino, C1-6alkylthio, C1-6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy. More preferably, R1a is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, di(C1-6alkyl)amino, halogen, trifluoromethyl and trifluoromethoxy. Most preferably, R1a is independently selected from the group consisting of methyl, ethyl and phenyl.
Embodiments of a compound of Formula (I) include those compounds wherein, preferably, R2 is selected from the group consisting of phenyl, naphthalenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indolyl, benzo[b]furyl and benzo[b]thienyl optionally substituted with one to three substituents independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, C1-3alkoxy, amino, C1-3alkylamino, di(C1-3alkyl)amino, C1-3alkylcarbonyl, C1-3alkylcarbonyloxy, C1-3alkylcarbonylamino, chlorine, fluorine, hydroxy, trifluoromethyl and trifluoromethoxy.
More preferably, R2 is selected from the group consisting of phenyl, furyl, thienyl, pyridinyl and benzo[b]furyl optionally substituted with one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylcarbonyl, methylcarbonyloxy, methylcarbonylamino, fluorine, hydroxy, trifluoromethyl and trifluoromethoxy.
Most preferably, R2 is selected from phenyl optionally substituted with one substituent selected from the group consisting of methoxy and hydroxy.
Embodiments of a compound of Formula (I) include those compounds wherein, preferably, R3 is selected from the group consisting of phenyl, naphthalenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indolyl, benzo[b]furyl and benzo[b]thienyl optionally substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, allyl, methoxy, ethoxy, amino, C1-3alkylamino, di(C1-3)alkylamino, C1-3alkylcarbonyl, C1-3alkylcarbonyloxy, C1-3alkylcarbonyl, C1-3alkylaminocarbonyl, C1-3alkylcarbonylamino, C1-3alkylthio, C1-3alkylsulfonyl, chloro, fluoro, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when phenyl is substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of xe2x80x94(CH2)3-5xe2x80x94 and xe2x80x94O(CH2)1-3Oxe2x80x94.
More preferably, R3 is phenyl substituted with the moiety -A-Z at the 3 or 4 position.
Embodiments of a compound of Formula (I) include those compounds wherein, preferably, A is xe2x80x94C(xe2x95x90X)xe2x80x94.
Embodiments of a compound of Formula (I) include those compounds wherein, preferably, Z is xe2x80x94N(R5)(R6).
An embodiment of a compound of Formula (I) includes those compounds wherein, preferably, R4 is selected from the group consisting of C1-8alkyl (optionally substituted with one to three halogen substituents), C2-8alkenyl, aryl and aryl(C1-8)alkyl; wherein aryl is optionally substituted with one to two substituents independently selected from the group consisting of C1-8alkyl, xe2x80x94OCH2Oxe2x80x94, xe2x80x94O(CH2)2Oxe2x80x94 and halogen.
More preferably, R4 is selected from the group consisting of C1-3alkyl (optionally substituted with one or three fluorine substituents), C2-4alkenyl, phenyl and benzyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C1-3alkyl, xe2x80x94OCH2Oxe2x80x94, xe2x80x94O(CH2)2Oxe2x80x94 and fluorine.
Most preferably, R4 is selected from the group consisting of methyl, ethyl, 3-methallyl, phenyl and benzyl; wherein phenyl is optionally substituted with one substituent selected from the group consisting of methyl and fluorine.
An embodiment of a compound of Formula (I) includes those compounds wherein, preferably, R5 and R6 are independently selected from the group consisting of hydrogen, C1-4alkyl, fluoro(C1-3)alkyl, trifluoro(C1-3)alkyl, C1-3alkoxy(C1-3)alkyl, C2-5alkenyl, cyclopropyl, cyclopropyl(C1-3)alkyl, cyclopentyl, cyclopentyl(C1-3)alkyl, cyclohexyl, cyclohexyl(C1-3)alkyl, pyrrolidinyl, pyrrolidinyl(C1-3)alkyl, 1,3-dioxolanyl, 1,3-dioxolanyl(C1-3)alkyl, 2-imidazolinyl, 2-imidazolinyl(C1-3)alkyl, imidazolidinyl, imidazolidinyl(C1-3)alkyl, 2-pyrazolinyl, 2-pyrazolinyl(C1-3)alkyl, pyrazolidinyl(C1-3)alkyl, piperidinyl, piperidinyl(C1-3)alkyl, morpholinyl, morpholinyl(C1-3)alkyl, thiomorpholinyl, thiomorpholinyl(C1-3)alkyl, piperazinyl, piperazinyl(C1-3)alkyl, piperonyl, phenyl, benzyl, phenyl(C2-3)alkyl, furyl, furyl(C1-3)alkyl, thienyl, thienyl(C1-3)alkyl, pyrrolyl(C1-3)alkyl, oxazolyl, oxazolyl(C1-3)alkyl, thiazolyl, thiazolyl(C1-3)alkyl, imidazolyl, imidazolyl(C1-3)alkyl, pyrazolyl, pyrazolyl(C1-3)alkyl, isoxazolyl, isoxazolyl(C1-3)alkyl, isothiazolyl, isothiazolyl(C13)alkyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl(C1-3)alkyl, 1,2,3-triazolyl, 1,2,3-triazolyl(C1-3)alkyl, 1,3,4-thiadiazolyl, 1,3,4-thiadiazolyl(C1-3)alkyl, pyridinyl, pyridinyl(C1-3)alkyl, pyridazinyl, pyridazinyl(C1-3)alkyl, pyrimidinyl, pyrimidinyl(C1-3)alkyl, pyrazinyl, pyrazinyl(C1-3)alkyl, 1,3,5-triazinyl, 1,3,5-triazinyl(C1-3)alkyl, indolyl(C1-3)alkyl, benzo[b]furyl, benzo[b]furyl(C1-3)alkyl, benzo[b]thienyl, benzo[b]thienyl(C1-3)alkyl, benzimidazolyl, benzimidazolyl(C1-3)alkyl, amino(C1-3)alkyl, C1-3alkylamino(C1-3)alkyl, di(C1-3)alkylamino(C1-3)alkyl, aminoimino, hydroxy(C1-3)alkyl and trifluoro(C1-4)alkoxy; wherein pyrrolidinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl are optionally substituted with one to three substituents independently selected from the group consisting of C1-4alkyl and oxo; and, wherein phenyl is optionally substituted with one to four substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, xe2x80x94OCH2Oxe2x80x94, xe2x80x94O(CH2)2Oxe2x80x94, halogen, hydroxy and cyano; alternatively, R5 and R6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety selected from the group consisting of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl optionally substituted with one to four substituents independently selected from C1-4alkyl.
More preferably, R5 and R6 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, t-butyl, fluoro(C1-3)alkyl, methoxy(C1-3)alkyl, methallyl, cyclopropyl, cyclohexyl, phenyl, thiazolyl, imidazolyl(C1-3)alkyl, benzimidazolyl(C1-3)alkyl, dimethylamino(C1-3)alkyl and hydroxy(C1-3)alkyl; wherein phenyl is optionally substituted with one to three substituents selected from fluorine; alternatively, R5 and R6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety selected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl optionally substituted with one to four substituents independently selected from the group consisting of methyl, ethyl, n-propyl and n-butyl.
Most preferably, R5 and R6 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, t-butyl, 2-fluoroethyl, methoxyethyl, methallyl, cyclopropyl, cyclohexyl, phenyl, thiazolyl, 2-(2-imidazolyl)ethyl, benzimidazolylmethyl, dimethylaminopropyl and hydroxyethyl; wherein phenyl is optionally substituted with fluorine; alternatively, R5 and R6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety selected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl; wherein piperidinyl is substituted with two or four substituents selected from methyl.
Table 1 lists compounds exemplified in the present invention of the formula:
and pharmaceutically acceptable enantiomers, diastereomers and salts thereof.
Table 2 lists compounds exemplified in the present invention of the formula:
and pharmaceutically acceptable enantiomers, diasteromers and salts thereof.
Instant compounds of the invention may also be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharic or trifluoroacetic.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The compounds of this invention are chiral and, thus, may exist as enantiomers. In addition, the compounds may exist as diastereomers. It is to be understood that all such enantiomers and diastereomers, as well as all mixtures thereof, are encompassed within the scope of the present invention.
Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention.
In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
The present invention also contemplates a pharmaceutical composition comprising a combination of a xcex4-opioid or xcexc-opioid receptor modulator compound of Formula (I) and a xcexc-opioid receptor modulator compound known to those skilled in the art or a xcex4-opioid or xcexc-opioid receptor modulator compound of Formula (I) wherein the combination has a synergistic therapeutic effect.
Suitable xcexc-opioid receptor modulator compounds known to those skilled in the art for use in such a combination include, without limitation, the compounds alfentanil, allylprodine, alphaprodine, anileridine, bezitramide, buprenorphine, clonitazene, cyclazocine, dextromoramide, dihydrocodeine, dihydromorphine, ethoheptazine, ethylmorphine, etonitazene, fentanyl, heroin, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, morphine, nalbuphine, norlevorphanol, normethadone, nalorphine, normorphine, opium, oxycodone, oxymorphone, phenazocine, piritramide, propiram, propoxyphene, sufentanil, tramadol and diastereomers, salts, complexes and mixtures thereof of any of the foregoing.
The terms used in describing the invention are commonly used and known to those skilled in the art. However, the terms that could have other meanings are hereinafter defined. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
An xe2x80x9cindependentlyxe2x80x9d selected substituent refers to a group of substituents, wherein the substituents may be different. Therefore, designated numbers of carbon atoms (e.g., C1-C6) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term xe2x80x9calkylxe2x80x9d refers to straight and branched-chain alkyl radical groups with 1 to 8 carbon atoms or any number within this range. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to radical groups having straight and branched chains with 2 to 8 carbon atoms or any number within this range. For alkenyl chains, one double bond is formed between adjacent members of a two or three carbon chain and one or two double bonds are formed between adjacent members of a four to eight carbon chain. For alkynyl chains, one triple bond is formed between adjacent members of a two or three carbon chain and one or two triple bonds are formed between adjacent members of a four to eight carbon chain. Correspondingly, the terms xe2x80x9calkylene,xe2x80x9d xe2x80x9calkenylenexe2x80x9d and xe2x80x9calkynylenexe2x80x9d refer to alkyl, alkenyl and alkynyl linking groups wherein alkyl, alkenyl and alkynyl are as defined supra. Preferably, alkenylene and alkynylene linking group chains have at least one saturated carbon atom on each side of the unsaturated bond. More preferably, when an aryl or heteroaryl substituent is attached to the terminal carbon of an alkenylene or alkynylene linking group, at least one saturated carbon atom is between the unsaturated bond and the substituent. The term xe2x80x9calkoxyxe2x80x9d refers to O-alkyl groups wherein alkyl is as defined supra.
Whenever the term xe2x80x9calkylxe2x80x9d appears in the name of a substituent (e.g., hydroxy(C1-6)alkyl) it shall be interpreted as including those limitations given above for xe2x80x9calkyl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-6) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term xe2x80x9ccycloalkylxe2x80x9d refers to branched or unbranched cyclic aliphatic hydrocarbon chains of three to seven carbon atom members. Examples of such cyclic alkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term xe2x80x9cheterocyclylxe2x80x9d refers to a nonaromatic cyclic ring of five to seven members in which one to four members are nitrogen or a nonaromatic cyclic ring of five to seven members in which zero, one or two members are nitrogen and one member is oxygen or sulfur; and in which,
a) optionally, the ring contains zero, one or two unsaturated bonds;
b) optionally, up to three carbon members adjacent to nitrogen members may be oxo substituted.
Optionally, the heterocyclyl ring is fused:
a) to a benzene ring;
b) to a 5 or 6 membered heteroaryl containing one of O, S or N and, optionally, one additional nitrogen;
c) to a 5 to 7 membered alicyclic ring;
d) to a 5 to 7 membered heterocyclyl ring of the same definition as above but absent the option of a further fused ring.
For instant compounds of the invention, the carbon atom ring members that form the heterocyclyl ring are fully saturated. Other compounds of the invention may have a partially saturated heterocyclyl ring. Preferred partially unsaturated heterocyclyl rings may have one or two double bonds. Such compounds are not considered to be fully aromatic and are not referred to as heteroaryl compounds. Therefore, a five member heterocyclyl ring may optionally have a double bond formed in the ring between adjacent ring members; a six or seven member heterocyclyl ring may have two double bonds formed in the ring between adjacent ring members.
The term aryl refers to a single aromatic ring of six carbon members or a bicyclic aromatic ring of ten carbon members. Examples of such aryl rings include phenyl and naphthyl.
The term heteroaryl refers to an aromatic ring of five or six members wherein the ring has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of five-membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to two additional nitrogens. In the case of six-membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the six member ring has three nitrogens, at most two nitrogen atoms are adjacent.
The terms xe2x80x9chalo1-3(C1-8)alkyl,xe2x80x9d xe2x80x9ccycloalkyl(C1-8)alkylxe2x80x9d or xe2x80x9chydroxy(C1-6)alkylxe2x80x9d refer to an alkylene group substituted at the terminal carbon with a halo, cycloalkyl or hydroxy group, respectively. Similarly, the term xe2x80x9cC1-8alkoxy(C1-8)alkenylxe2x80x9d or xe2x80x9cC1-8alkoxy(C1-8)alkynylxe2x80x9d refers to an alkenylene or alkynylene group substituted at the terminal carbon with an alkoxy group. The term xe2x80x9ccarbonylxe2x80x9d refers to the linking group xe2x80x94Cxe2x95x90Oxe2x80x94. Furthermore, the term xe2x80x9cmethylenedioxyxe2x80x9d refers to the substituent moiety xe2x80x94OCH2Oxe2x80x94, the term xe2x80x9cethylenedioxyxe2x80x9d refers to the substituent moiety xe2x80x94O(CH2)2Oxe2x80x94 and the term xe2x80x9ctrimethylenedioxyxe2x80x9d refers to the substituent moiety xe2x80x94O(CH2)3Oxe2x80x94. The term xe2x80x9chydroxyxe2x80x9d refers to the group xe2x80x94OH and the term xe2x80x9coxoxe2x80x9d refers to the group xe2x95x90O. The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to the group iodine, bromine, chlorine and fluorine.
Where the compounds according to this invention are chiral, they may accordingly exist as enantiomers. In addition, the compounds may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The terms used in describing the invention are commonly used and known to those skilled in the art. As used herein, the following abbreviations have the indicated meanings:
Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated in the schemes that follows. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
Scheme 1 describes a general scheme for the preparation of certain target 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives of the invention using synthetic methods to prepare intermediate compounds also intended to be within the scope of the present invention.
A Suzuki reaction is used to couple a boronic acid Compound 1a with an iodinated Compound 1b in the presence of carbon monoxide to produce an intermediate Compound 1c. Alternatively, Compound 1b may also be substituted with bromine or OTF (trifluoromethylsulfonyloxy) in place of iodine. For Compound 1a and Compound 1b, the R2 and R3 substituents and -A-Z moiety may be varied by using appropriate starting materials or may be added in later steps.
For example, the -A- portion of the -A-Z moiety may be varied using xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94SO2xe2x80x94 (more preferably, xe2x80x94C(xe2x95x90O)xe2x80x94) and the -Z- portion of the -A-Z moiety may be varied using xe2x80x94OH, xe2x80x94O(R4) or xe2x80x94N(R5)(R6) (more preferably, xe2x80x94O(R4) or xe2x80x94N(R5)(R6)) to produce other intermediate compounds of the present invention. Similarly, target compounds wherein Z is xe2x80x94O(R4) and R4 is hydrogen may be conveniently produced by conventional hydrolysis of the Z is xe2x80x94N(R5)(R6) group; furthermore, other compounds wherein Z is xe2x80x94O(R4) and R4 is hydrogen may be esterified by conventional methods to produce other target compounds wherein R4 is C1-8alkyl.
A Robinson-Schxc3x6pf condensation is used to prepare tropinone intermediate Compounds 1e bearing an R1 substituent on nitrogen by mixing an R1 substituted amine Compound 1e with a succinaldehyde precursor such as 2,5-dimethoxytetrahydrofuran and acetonedicarboxylic acid. For a Compound 1e, the R1 substituent may be varied by using appropriate starting materials or may be added in later steps.
Compound 1c and Compound 1e may be coupled using a titanium mediated xe2x80x9cMcMurrayxe2x80x9d reaction to produce a target Compound 1f. 
Scheme 2 describes another general scheme for the preparation of certain 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives.
As shown below in Scheme 2, the intermediate Compound 1c may be coupled with an 8-methyl-8-azabicyclo[3:2:1]octanone compound using titanium mediated coupling to produce an intermediate Compound 2a.
The intermediate Compound 2a may be treated with 2,2,2-trichloroethyl chloroformate followed by reflux with zinc powder in MeOH to obtain the N-demethylated Compound 2b. Compound 2c is produced by alkylation of Compound 2b with an alkyl halide or reductive alkylation with sodium triacetoxyborohydride and a carbonyl compound.
As desired, the identity of the -A-Z moiety may be varied by conversion of one -A-Z moiety to another. For example, an -A-Z moiety where the -A- portion is xe2x80x94C(xe2x95x90O)xe2x80x94 and the -Z- portion is xe2x80x94O(R4), the -Z- portion may be hydrolyzed to the acid, wherein xe2x80x94O(R4) becomes xe2x80x94OH. Subsequently, the resulting carboxyl group may be converted to the desired amide; and, conversely, an amide group may be hydrolyzed to an acid. 
As shown in Scheme 3, a Compound 3a wherein X is O may also be further treated with a suitable thionating agent such as P2S5 or Lawesson""s Reagent to prepare a Compound 3b wherein X is S. 
The compounds of the present invention may be used to treat mild to moderately severe pain in warm-blooded animals such as humans by administration of an analgesically effective dose. The dosage range would be from about 0.01 mg to about 15,000 mg, in particular from about 0.1 mg to about 3500 mg or, more particularly from about 0.1 mg to about 1000 mg of active ingredient in a regimen of about 1 to 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the types of pain being treated.
Examples of pain intended to be within the scope of the present invention include, but are not limited to, centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain such as caused by acute injury, trauma or surgery and chronic pain such as caused by neuropathic conditions, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain syndromes or cluster or migraine headaches.
In regard to the use of the present compounds as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, a therapeutically effective dose can be determined by persons skilled in the art by the use of established animal models. Such a dose would likely fall in the range of from about 0.01 mg to about 15,000 mg of active ingredient administered 1 to 4 times per day for an average (70 kg) human.
Pharmaceutical compositions of the invention comprise the formula (I) compounds as defined above, particularly in admixture with a pharmaceutically acceptable carrier. Illustrative of the invention, therefore, is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Another illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. A further illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the invention or salt thereof, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
Specific compounds which are representative of this invention may be prepared as per the following examples offered by way of illustration and not by way of limitation. For the sake of clarity, bracketed numbers following compound names indicate the stoichiometric salt associated with the compound, which is further exemplified by the calculated analytical data. Also, examples specifically used to prepare intermediates for the further synthesis of compounds of the invention are designated by xe2x80x9cProcedure.xe2x80x9d As well, instant compounds may also be used as starting materials in subsequent examples to produce additional compounds of the present invention. No attempt has been made to optimize the yields obtained in any of the reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.
A solution of 25 g (110 mmol) 4-benzoylbenzoic acid [611-95-0] and 20 mL SOCl2 was allowed to reflux for 2 h then allowed to cool. The excess SOCl2 was evaporated off and the resulting clear oil was dissolved in 10 mL CH2Cl2 then slowly added to 12 mL (116 mmol) diethylamine in a mixture of 10 mL 3N NaOH and 50 mL CH2Cl2. The mixture was allowed to stir for 30 min then partitioned between H2O and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered and concentrated. The product precipitated from EtOAc/hexane to give 29.6 g (105 mmol) white crystals. MS m/z (MH+) 282.